Optically active pyrrolidine compound and method for producing same

ABSTRACT

The present invention provides: a methyl 1-{2-[(3S,4R)-1-[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl) pyrrolidine-3-carbonyl]-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl) phenyl}piperidine-4-carboxylate 1/2 ethane-1,2-disulfonic acid which is represented by formula (1) and is excellent in crystallinity; and a method for producing the same; and a production intermediate thereof; and a production method using this compound.

TECHNICAL FIELD

The present invention relates to methyl1-{2-[(3S,4R)-1-[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-carbonyl]-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylate1/2 ethane-1,2-disulfonic acid, which has excellent crystallinity(hereinafter, referred to as “Present compound” or “compound of thepresent invention”), a method for preparing the same, and a productionintermediate thereof, as well as a method for production of a particularproduct using the same.

BACKGROUND ART

The Patent Document 1 describes compounds which has melanocortinreceptor activation activity and is useful for prophylaxis or treatmentof various diseases or conditions in which an activation of melanocortinreceptor is involved, and a method for preparing the compounds, and alsodescribes dihydrochloride salts of a compound represented by formula(11) below in Example 19.

However, the Patent Document 1 doesn't disclose specifically thecompounds described herein including the above-mentioned presentcompound, and the method for preparing these compounds.

Also the Patent Documents 2 to 9 and non-Patent Documents 1 to 3describe a method for preparing optically active pyrrolidine derivativesby a cyclization reaction of styrene derivatives with the tertiary amineusing 4-phenyl-2-oxazolidinone as an asymmetric auxiliary group.However, a cyclization reaction of styrene derivatives with the tertiaryamine as described in the present application isn't described.

CITATION LIST Patent Document

Patent Document 1: WO 2015/182723

Patent Document 2: WO 2001/047879

Patent Document 3: WO 2001/047905

Patent Document 4: WO 2001/047914

Patent Document 5: WO 2012/118850

Patent Document 6: WO 2014/078372

Patent Document 7: WO 2014/078378

Patent Document 8: WO 2014/078323

Patent Document 9: WO 2016/021629

Non-Patent Document

Non-Patent Document 1: Tetrahedron: Asymmetry 1997, Vol. 8, No. 6,883-887

Non-Patent Document 2: Tetrahedron: Asymmetry 1999, Vol. 10, 2605-2616

Non-Patent Document 3: Organic Letters 2006, Vol. 8, No. 7, 1495-1498

SUMMARY OF THE INVENTION Problems to be Solved by Invention

In a preparation of an active pharmaceutical ingredient, a strictquality control of intermediate compounds, etc., is required as the endof the overall steps is being approached, and there is thus a need toalways get a consistent quality of compound. Accordingly, if anintermediate compound can be obtained in a crystal form, it is possibleto isolate and purify by a processing operation with easy operabilitysuch as crystallization and recrystallization, which is preferable inaspects of a quality control. Compounds having excellent crystallinityalso have an advantage in that accurate weighing is possible.

The purpose of the present invention is to provide salts of methyl1-{2-[(3S,4R)-1-[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-carbonyl]-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylate,which has excellent crystallinity, and a method showing excellentstereoselectivity for preparing the compound.

Means to Solve Problems

The present invention includes the followings [1] to [11], however,which are not limited thereto.

[1] Methyl1-{2-[(3S,4R)-1-[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-carbonyl]-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylate1/2 ethane-1,2-disulfonic acid, which is represented by formula (1):

[1-2] A crystal of the compound according to [1] which has as adiffraction angle (2θ±0.2°) diffraction peaks of at least 8.298, 14.198,16.776, 17.102, 20.972, 22.658, 24.959.[2] A method for preparing the compound (1), which is shown by thereaction scheme:

wherein

R¹ represents a protecting group for an amino group which is an alkylhaving one to six carbon atom(s) which may be optionally substitutedwith aryl in which the aryl may be optionally substituted with alkoxyhaving one to six carbon atoms,

R² represents a silyl which is substituted with one to three alkylhaving one to six carbon atoms or a cyano, and

R³ represents an alkoxy having one to six carbon atoms.

, wherein the method comprises the following steps:

(a) a step of reacting a compound (2-a) with a compound (3) to obtain acompound (4-a) or salts thereof,(b) a step of hydrolyzing a compound (4-a) or salts thereof to obtain acompound (5-a) or salts thereof,(c) a step of removing a protecting group R¹ of an amino group in thecompound (5-a) or salts thereof, followed by reacting with a compound(6) to obtain a compound (7-a) or salts thereof,(d) a step of condensing the compound (7-a) or salts thereof with acompound (8) or salts thereof to obtain a compound (1′) or saltsthereof, and(e) a step of reacting the compound (1′), or the compound (1′) which isobtained by desalting of a salt of the compound (1′), with a compound(9) to obtain a compound (1).[3] The method according to [2] wherein R¹ represents a benzyl, R²represents a trimethylsilyl, and R³ represents a methoxy.[4] A compound represented by formula (4):

wherein

R⁴ represents an alkyl having one to six carbon atoms which may beoptionally substituted with aryl in which the aryl may be optionallysubstituted with alkoxy having one to six carbon atoms,

or salts thereof.[5] A compound represented by formula (4-a):

wherein the symbols are the same as defined in [4], or salts thereof.[6] A compound represented by formula (5):

wherein

R⁵ represents an alkyl having one to six carbon atoms which may beoptionally substituted with aryl in which the aryl may be optionallysubstituted with alkoxy having one to six carbon atoms,

or salts thereof.[7] A compound represented by formula (5-a):

wherein the symbol is the same as defined in [6], or salts thereof.[8] A compound represented by formula (2):

or salts thereof.[9] A compound represented by formula (2-a):

or salts thereof.[10] A compound (1′):

or salts thereof.[11] A method for preparing a compound represented by formula (11):

or pharmaceutically acceptable salts thereof, which comprisesa step of hydrolyzing methyl1-{2-[(3S,4R)-1-[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-carbonyl]-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylate1/2 ethane-1,2-disulfonic acid or salts thereof, and optionally, asneeded, a step of subjecting to a salt-forming treatment.

In [11], as methyl1-{2-[(3S,4R)-1-[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-carbonyl]-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylate1/2 ethane-1,2-disulfonic acid, those obtained by the method accordingto [2] or [3] is preferably used.

Effect of Invention

The present invention can provide methyl1-{2-[(3S,4R)-1-[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-carbonyl]-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylate1/2 ethane-1,2-disulfonic acid, which has excellent crystallinity.Further, the present invention can provide a method showing excellentstereoselectivity for preparing the same compound, and a productionintermediate compound of the same compound, and a method using the samecompound for preparing compounds which is useful for prophylaxis ortreatment of various diseases or conditions in which an activation ofmelanocortin receptor is involved.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows a powder X-ray diffraction pattern of methyl1-{2-[(3S,4R)-1-[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-carbonyl]-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylate1/2 ethane-1,2-disulfonic acid which is obtained by Example 7.

MODE FOR CARRYING OUT THE INVENTION

The definition of each group described herein can be freely combined asdesired, unless otherwise specified.

As used herein, the “alkyl having one to six carbon atom(s)” refers to astraight or branched saturated hydrocarbon chain group having one to sixcarbon atom(s) (C₁₋₆). Alkyl having one to four carbon atom(s) (C₁₋₄) isparticularly preferable. Specific examples thereof include methyl,ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, 2-methyl-n-butyl,i-amyl (i.e., 3-methyl-n-butyl), and 2-methyl-n-pentyl and the others.Preferable specific examples thereof include methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl and t-butyl.

As used herein, the “alkoxy having one to six carbon atom(s)” refers toa monovalent group in which the above-described alkyl group having oneto six carbon atom(s) is attached to an oxygen atom, for example, astraight or branched alky-O— having one to six carbon atom(s) (C₁₋₆),and alky-O— having one to four carbon atom(s) (C₁₋₄) is particularlypreferable. Specific examples thereof include methoxy, ethoxy,n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, 2-methyl-n-butoxy,i-amyloxy (i.e., 3-methyl-n-butoxy), 2-methyl-n-pentoxy and the others.Preferable specific examples thereof include methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, i-butoxy, t-butoxy.

As used herein, the “aryl” refers to six to ten membered monocyclicaromatic hydrocarbon group or fused bicyclic aromatic hydrocarbon group.Specific examples of the monocyclic aromatic hydrocarbon group includephenyl and the others, and specific examples of the fused bicyclicaromatic hydrocarbon group include naphthyl and the others.

As used herein, the “salt-forming treatment” refers to a treatment forforming a salt of compound (including a pharmaceutically acceptablesalt) with the corresponding acid. Examples of the corresponding acidsinclude inorganic acids (such as hydrochloric acid, sulfuric acid,phosphoric acid, hydrobromic acid, and the others); and organic acids(such as acetic acid, oxalic acid, malonic acid, 2-methylmalonic acid,succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid,dibenzoyl tartaric acid, citric acid, methanesulfonic acid,benzenesulfonic acid, ethanedisulfonic acid, tosylic acid and theothers).

As used herein, examples of “salt(s) of compound” include inorganic acidsalts (such as hydrochloride salt, sulfate, phosphate, hydrobromide saltand the others); and organic acid salts (such as acetate, oxalate,malonate, 2-methylmalonate, succinate, fumarate, malenate, malate,tartrate, dibenzoyltartrate, citrate, methanesulfonate,benzenesulfonate, ethanedisulfonate, tosylate and the others).

As used herein, examples of “pharmaceutically acceptable salt(s)”include inorganic acid salts (such as hydrochloride salt, sulfate salt,phosphate salt, hydrobromide salt and the others); and organic acidsalts (such as acetate, fumarate, oxalate, citrate, methanesulfonate,benzenesulfonate, tosylate, malenate and the others).

Embodiment

In the present invention, preferable aspects are described below.

R¹, R⁴ and R⁵ may be a protecting group of amino group which is stablein the presence of acid, and includes specifically, an alkyl having oneto six carbon atoms which may be optionally substituted with aryl inwhich the aryl may be optionally substituted with alkoxy having one tosix carbon atoms, and includes preferably an alkyl group having one tosix carbon atoms, a benzyl or 1-phenethyl each of which may beoptionally substituted with alkoxy having one to six carbon atoms, andmore preferably, methyl, ethyl, benzyl, p-methoxybenzyl and 1-phenethyl,and particularly preferably, benzyl.

Examples of “alkyl having one to six carbon atoms” in the term of “alkylhaving one to six carbon atoms which may be optionally substituted witharyl in which the aryl may be optionally substituted with alkoxy havingone to six carbon atoms” for R¹, R⁴ and R⁵ include preferably methyl andethyl, and more preferably methyl.

Examples of “aryl” in the term of “alkyl having one to six carbon atomswhich may be optionally substituted with aryl in which the aryl may beoptionally substituted with alkoxy having one to six carbon atoms” forR¹, R⁴ and R⁵ include preferably phenyl.

Examples of “alkoxy having one to six carbon atoms” in the term of“alkyl having one to six carbon atoms which may be optionallysubstituted with aryl in which the aryl may be optionally substitutedwith alkoxy having one to six carbon atoms” for R¹, R⁴ and R⁵ includepreferably methoxy.

Examples of R² include a silyl which may be optionally substituted withone to three of alkyl having one to six carbon atom(s), or a cyano, andinclude preferably trialkylsilyl or cyano, more preferablytrimethylsilyl or cyano, and particularly trimethylsilyl.

Examples of R³ include an alkoxy having one to six carbon atoms, andpreferably methoxy.

As one aspect of the present invention, a method comprising at least onesteps selected from the following preparation steps (A) to (F) isincluded.

(A) a step of reacting a compound represented by formula (2-a) with acompound represented by formula (3) to prepare a compound represented byformula (4-a) (or salts thereof)

wherein R¹, R² and R³ are the same as defined above.

A reaction of the compound represented by formula (2-a) with thecompound represented by formula (3) can be conducted in the presence ofan appropriate catalyst in an appropriate solvent.

The catalyst may be any substances for providing proton, and includesfor example, acids (such as inorganic acids or organic acids), andincludes preferably, trifluoroacetic acid and trichloroacetic acid, andmore preferably trifluoroacetic acid. Alternatively, the catalyst may beany substances for providing fluoride ion, and includes for example,tetrabutylammonium fluoride.

A solvent may be anything that does not disturb the reaction, andexamples thereof include ethers (such as tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, 1,1-diethoxypropane, 1,1-dimethoxymethane,2,2-dimethoxypropane); halogenated aromatic hydrocarbons (such aschlorobenzene); halogenated aliphatic hydrocarbons (such as chloroform,1,2-dichloroethene and dichloromethane); acetonitrile,dimethylformamide; and mixture of two or more of these solvents.

A reaction temperature of the present reaction is varied depending onused reagent(s) or used reaction condition (for example, usedsolvent(s)), and is usually under cooling to under heating, preferably 0to 40° C., and more preferably 25° C.

A reaction period of the present reaction is varied depending on usedreagent(s) or used reaction condition (for example, used solvent(s)),and is usually from 30 minutes to 2 hours, and preferably 1 hour.

Also the mixed amount of the compound represented by formula (3) iswithin a range of usually 1 to 3 molar equivalent(s) and preferably 1.8molar equivalents, as opposed to 1 mole equivalent of the compoundrepresented by formula (2).

The mixed ratio of the catalyst to the compound of formula (2) is withinthe range of usually 0.01 to 1 molar equivalent(s), and preferably 0.1molar equivalents.

The present reaction may be conducted under inert gas, for example,under nitrogen gas or argon gas.

In the reaction of the compound represented by formula (2-a) with thecompound represented by formula (3), the following compound(hereinafter, referred to as compound represented by formula (4-b)) maybe obtained as a by-product. The compound represented by formula (4-a)and the compound represented by formula (4-b) have diastereomericrelationships to each other.

wherein R¹ is the same as defined above.

Examples of the method for separating the compound represented byformula (4-a) and the compound represented by formula (4-b) includecrystallization, recrystallization, chroromatography and the others, andtwo or more thereof may be combined.

Specific examples of crystallization method includes a method in which amixture of the compound represented by formula (4-a) and the compoundrepresented by formula (4-b) is dissolved in ethers (such as1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, 1,1-diethoxypropane,1,1-diethoxymethane and 2,2-dimethoxypropane); halogenated aromatichydrocarbons (such as chlorobenzene); or halogenated aliphatichydrocarbons (such as chloroform, 1,2-dichloroethene anddichloromethane), and then alcohols (such as methanol, ethanol,1-propanol, 2-propanol, 1-butanol, 2-butanol, 3-methyl-1-butanol,2-methyl-1-propanol and 1-pentanol); or ketones (such as acetone) isthen added thereto. Preferable examples of the method include a methodin which a mixture of the compound represented by formula (4-a) and thecompound represented by formula (4-b) is dissolved in1,2-dimethoxyethane, and methanol is then added thereto.

(B) a step for preparing a compound represented by formula (5-a) (orsalts thereof) from the compound represented by formula (4-a) (or saltsthereof)

wherein, R¹ is the same as defined above.

In the reaction for obtaining the compound represented by formula (5-a)from the compound represented by formula (4-a), the following compoundrepresented by formula (5-b) may be obtained as a by-product. Thecompound represented by formula (5-a) and the compound represented byformula (5-b) have enantiomeric relationships to each other.

wherein R¹ is the same as defined above.

Examples of a method for separating the compound represented by formula(5-a) and the compound represented by formula (5-b) include an opticalresolution (such as crystallization, recrystallization andchromatography), and two or more thereof may be combined.

The compound represented by formula (5-a) (or salts thereof) may beobtained by hydrolyzing the compound represented by formula (4-a) (orsalts thereof) in an appropriate solvent.

A solvent may be anything that does not disturb the present reaction,and examples of the solvent include alcohols (such as methanol, ethanol,1-propanol, 2-propanol, 1-butanol, 2-butanol, 3-methyl-1-butanol,2-methyl-1-propanol and 1-pentanol); ketones (such as acetone, methylethyl ketone, methyl isopropyl ketone, methyl butyl ketone and methylisobutyl ketone); ethers (such as 1,2-dimethoxyethane, 1,4-dioxane,1,1-dimethoxymethane and methyltetrahydrofuran); amides (such asN,N-dimethylformamide and N,N-dimethylacetamide); N-methylpyrrolidone,acetonitrile and dimethylsulfoxide; and mixtures of two or more of thesesolvents.

Preferable examples of hydrolysis include a hydrolysis in the presenceof a base.

Examples of the base include inorganic bases (such as lithium hydroxide,sodium hydroxide and potassium hydroxide).

A reaction temperature of the present reaction is varied depending onused reagent(s) or used reaction condition (for example, usedsolvent(s)), and is usually under cooling to under heating, preferably 0to 30° C., and more preferably 0° C.

A reaction period of the present reaction is varied depending on usedreagent(s) or used reaction condition (for example, used solvent(s)),and is usually from 1 hour to 6 hours, and preferably 3 hours.

Also the additive amount of the base is within a range of 1 to 2 molarequivalent(s) and preferably 1.2 molar equivalents, as opposed to 1 moleequivalent of the compound represented by formula (4-a).

The present reaction may be conducted under inert gas, for example,under nitrogen gas or argon gas.

(C) a step for reacting the compound represented by formula (5-a) (orsalts thereof) with a compound represented by formula (6) to prepare acompound represented by formula (7-a)

wherein R¹ is the same as defined above.

The compound represented by formula (7-a) can be obtained by reactingthe compound represented by formula (5-a) with the compound representedby formula (6) in the presence of an appropriate reductive agent in anappropriate solvent

In the reaction of the compound represented by formula (5-a) with thecompound represented by formula (6), the following compound representedby formula (7-b) may be obtained as a by-product. The compoundrepresented by formula (7-a) and the compound represented by formula(7-b) have enantiomeric relationships to each other.

Examples of a method for separating the compound represented by formula(7-a) and the compound represented by formula (7-b) include opticalresolution (such as crystallization, recrystallization andchromatography), and two or more thereof may be combined.

Examples of the reductive agent include a combination of a transitionmetal selected from nickel, palladium, rhodium, platinum or ruthenium,and a hydrogen source such as hydrogen gas. The transition metalsinclude simple substances of metal, or metals supported on carriers(such as carbon (such as activated carbon), zeolite, alumina, and silicagel). Preferable examples of the transition metals include palladium.Preferable examples of the carriers include carbon.

A solvent may be anything that does not disturb the present reaction,and examples of the solvent include alcohols (such as methanol, ethanol,1-propanol, 2-propanol, 1-butanol, 2-butanol, 3-methyl-1-butanol,2-methyl-1-propanol and 1-pentanol); ethers (such as1,2-dimethoxyethane, 1,4-dioxane, 1,1-diethoxypropane,1,1-dimethoxymethane, 2,2-dimethoxypropane, tetrahydrofuran andmethyltetrahydrofuran), and mixtures of two or more thereof.

A reaction temperature of the present reaction is varied depending onused reagent(s) or used reaction condition (for example, usedsolvent(s)), and is usually under cooling to under heating, preferably40 to 60° C., and more preferably 50° C.

A reaction period of the present reaction is varied depending on usedreagent(s) or used reaction condition (for example, used solvent(s)),and is usually from 3 hours to 24 hours, and preferably 20 hours.

Also the additive amount of the reducing agent is within a range of 0.01to 0.1 molar equivalents and preferably 0.016 molar equivalents, asopposed to 1 mole equivalent of the compound represented by formula(5-a).

Also the mixed amounts of the compound represented by formula (6) iswithin a range of usually 1 to 5 molar equivalent(s) and preferably 2.6molar equivalents, as opposed to 1 molar equivalent of the compoundrepresented by formula (5-a).

(D) a step of reacting the compound represented by formula (7-a) (orsalts thereof) with a compound represented by formula (8) (or saltsthereof) to prepare a compound represented by formula (1′) (or saltsthereof)

The compound represented by formula (1′) can be obtained by subjectingto a condensation reaction of the compound represented by formula (7-a)with the compound represented by formula (8) in the presence of anappropriate base and an appropriate condensation agent in an appropriatesolvent.

Examples of the base include amines (such as diisopropylethylamine andtriethylamine), and preferably diisopropylethylamine or triethylamine,and more preferably diisopropylethylamine.

Examples of the condensation agent include alkylphosphonic acidanhydrides (such as propylphoshonic acid anhydride); carbodiimides (suchas N,N′-dicyclohexyl carbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt, and1,1′-carbonyldiimidazole), and preferably propylphoshonic acidanhydride.

A solvent may be anything that does not disturb the present reaction,and examples of the solvent include aromatic hydrocarbons (such astoluene); hydrogenated aromatic hydrocarbons (such as chlorobenzene);halogenated aliphatic hydrocarbons (such as chloroform,1,2-dichloroethene and dichloromethane); ethers (such as t-butyl methylether and diethyl ether); esters (such as ethyl acetate, isobutylacetate, isopropyl acetate, propyl acetate and n-butyl acetate);acetonitrile; and mixtures of two or more thereof.

A reaction temperature of the present reaction is varied depending onused reagent(s) or used reaction condition (for example, usedsolvent(s)), and is usually under cooling to under heating, preferably 0to 30° C., and more preferably 10° C.

A reaction period of the present reaction is varied depending on usedreagent(s) or used reaction condition (for example, used solvent(s)),and is usually from 3 hours to 24 hours, and preferably 13 hours.

Also the additive amount of the base is within a range of usually 2 to 5molar equivalent(s) and preferably 3.5 molar equivalents, as opposed to1 mole equivalent of the compound represented by formula (7-a).

Also the additive amount of the condensation agent is within a range ofusually 1 to 2 molar equivalent(s) and preferably 1.5 molar equivalents,as opposed to 1 mole equivalent of the compound represented by formula(7-a).

Further the mixed amount of the compound represented by formula (8) iswithin a range of usually 1 to 1.2 molar equivalent(s) and preferably1.05 molar equivalents, as opposed to 1 mole equivalent of the compoundrepresented by formula (7-a).

(E) a step of reacting the compound represented by formula (1′) (orsalts thereof) with a compound represented by formula (9) to prepare acompound represented by formula (1)

The compound represented by formula (1) can be obtained by reacting thecompound represented by formula (1′) with a compound represented byformula (9) under an appropriate condition.

The compound represented by formula (1) can be obtained in a crystallineform by crystalizing it in alcohols. Examples of the alcohols includepreferably alcohols (such as methanol, ethanol, 1-propanol, 2-propanol,n-butyl alcohol, isobutyl alcohol and t-butyl alcohol), more preferablyethanol and isopropanol, and particularly preferably isopropanol.

A reaction temperature of the present reaction is varied depending onused reaction condition (for example, used solvent(s)), and ispreferably 50 to 85° C., and more preferably 75° C.

A reaction period of the present reaction is varied depending on usedreaction condition (for example, used solvent(s)), and is usually from 1hour to 5 hours, and preferably 1 hour.

The additive amount of the compound (9) as opposed to that of thecompound (1′) is within a range of usually 0.5 to 0.6 molar equivalents,and preferably 0.5 molar equivalents.

(F) a step for preparing a compound represented by formula (11) from thecompound represented by formula (1)

The compound represented by formula (11) can be obtained by as needed,subjecting salts of the compound represented by formula (1) to adesalting treatment, followed by hydrolyzing the resulting product in anappropriate solvent.

A solvent may be anything that does not disturb the present reaction,and examples of the solvents include alcohols (such as methanol,ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol,3-methyl-1-butanol, 2-methyl-1-propanol and 1-pentanol); ethers (such astetrahydrofuran, methyltetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethaneand 1,1-dimethoxymethane); ketones (such as acetone, methyl ethylketone, methyl butyl ketone, methyl isobutyl ketone and methyl isopropylketone); amides (such as N,N-dimethylacetamide andN,N-dimethylformamide); dimethylsulfoxide, N-methylpyrrolidone andacetonitrile; and mixtures of two or more thereof.

Preferable examples of the hydrolysis include a hydrolysis in thepresence of a base.

Examples of the base include inorganic bases (such as lithium hydroxide,sodium hydroxide and potassium hydroxide).

A reaction temperature of the present reaction is varied depending onused reaction condition (for example, used solvent(s)), and is usuallyunder cooling to under heating, preferably 10 to 45° C., and morepreferably 40° C.

A reaction period of the present reaction is varied depending on usedreaction condition (for example, used solvent(s)), and is usually from 3to 8 hours, and preferably 4 hours or 5 hours and more preferably 5hours.

Also an additive amount of the base as opposed to 1 molar equivalent ofthe compound represented by formula (1) is within a range of 1 to 2molar equivalent(s), preferably 1.1 or 1.5 molar equivalents, and morepreferably 1.1 molar equivalents.

EXAMPLES

Hereinafter, the present invention is explained in more detail by usingthe following Preparation Examples and Examples and the like, however,the present invention should not be limited to these examples.

As used herein, “Me” refers to methyl, “Et” refers to ethyl, “Ph” refersto phenyl, “Bn” refers to benzyl, and

“TMS” refers to trimethylsilyl.

Example 1

To a solution of the compound (13) (65.0 kg) in tetrahydrofuran (108.0kg) were added diazabicycloundecene (40.8 kg) and tetrahydrofuran (13.4kg) while stirring the solution at room temperature. The compound (12)(30.4 kg) and tetrahydrofuran (13.4 kg) were added thereto at 10° C.,the reaction mixture was then stirred at room temperature for 21 hours.Ethanol (119.8 kg) and 7.4% aqueous sodium hydroxide solution (358.2 kg)were added thereto at room temperature, and the mixture was stirred for2 hours. Water (137.7 kg), 35% hydrochloric acid (69.0 kg) and water(15.2 kg) were added thereto in that order at room temperature, and themixture was stirred at room temperature for 30 minutes and at 0° C. for1 hour. The crystals were collected by filtration, and washed with amixed solution of ethanol (24.0 kg) and water (60.9 kg), and furtherwith water (151.9 kg). The crystals were dried at 60° C. or less toobtain the compound (14) (28.6 kg) (yield 65%). MS (ESI): m/z 195.1[M−H]⁻

Example 2

To a mixture solution of the compound (14) (28.4 kg) in1,2-dimethoxyethane (124.4 kg) and N,N-dimethylformamide (1.06 kg) wereadded at 55° C. thionyl chloride (20.8 kg) and 1,2-dimethoxyethane (24.7kg), and the mixture was stirred for 2 hours. The mixture was cooled toroom temperature, and lithium chloride (6.76 kg), the compound (15)(23.6 kg) and 1,2-dimethoxyethane (24.8 kg) were added thereto in thatorder, and the mixture was raised to 55° C. N,N-diisopropylethylamine(46.8 kg) and 1,2-dimethoxyethane (24.7 kg) were added thereto, and themixture was stirred at 55° C. for 4 hours and at room temperature for 9hours. The mixed solution of methanol (22.4 kg) and water (114.2 kg) wasadded thereto at room temperature, and the mixture was stirred at roomtemperature for 30 minutes. The crystals were collected by filtration,and the crystals were washed with a mixed solution of water (28.4 kg)and 1,2-dimethoxyethane (49.4 kg). The crystals were dried at 60° C. orless to obtain the compound (2-a) (42.2 kg) (yield 85%). ¹H NMR(DMSO-d₆) 7.65-7.67 (m, 2H), 7.45-7.47 (m, 2H), 7.39-7.42 (m, 2H),7.33-7.36 (m, 1H), 7.03-7.06 (m, 2H), 7.01 (d, 1H), 5.59 (t, 1H), 4.85(t, 1H), 4.24 (t, 1H), 3.81 (s, 3H), MS (ESI): m/z 342.0 [M+H]⁺

Example 3

To a solution of the compound (2-a) (42.1 kg) in tetrahydrofuran (243.1kg) were added trifluoroacetic acid (1.41 kg), the compound (16) (52.7kg) and tetrahydrofuran (19.0 kg) in that order at room temperature, andthe reaction mixture was stirred for 2 hours. Methanol (466.6 kg) wasadded thereto at room temperature, and the mixture was stirred at 0° C.for 30 minutes. The crystals were collected by filtration and thecrystals were washed with 0° C. mixed solution of tetrahydrofuran (26.1kg) and methanol (43.5 kg), and further with 0° C. methanol (66.5 kg).The crystals were dried at 50° C. or less to obtain the crude product ofthe compound (17-a). A mixture of the obtained crude product and1,2-dimethoxyethane (164.9 kg) was stirred at 80° C. for 30 minutes, andafter the mixture was cooled to 35° C., methanol (150.0 kg) was addedthereto, and the mixture was stirred for 30 minutes. The crystals werecollected by filtration and the crystals were washed with a mixedsolution of 1,2-dimethoxyethane (36.6 kg) and methanol (33.3 kg). Thecrystals were dried at 50° C. or less to obtain the compound (17-a)(33.4 kg) (yield 57%). ¹H NMR (DMSO-d₆) 7.29-7.42 (m, 7H), 7.23-7.29 (m,3H), 7.17 (d, 2H), 6.82-6.85 (m, 2H), 5.42 (dd, 1H), 4.75 (dd, 1H), 4.20(dd, 1H), 4.12 (ddd, 1H), 3.73 (s, 2H), 3.71 (s, 3H), 3.61 (dd, 1H),3.19 (dd, 1H), 3.06 (dd, 1H), 2.83 (dd, 1H), MS (ESI): m/z 475.5 [M+H]⁺

Example 4

A solution of the compound (17-a) (33.3 kg) in tetrahydrofuran (148.0kg) was cooled to 5° C., and a solution of lithium hydroxide monohydrate(3.53 kg) in water (33.3 kg) and water (16.7 kg) was added thereto, andthe reaction mixture was stirred at 5° C. for 3.5 hours and at roomtemperature for 30 minutes. Thirty-five (35) % hydrochloric acid (8.68kg) was added thereto at room temperature, and the mixture was stirredfor 1 hour. The crystals were collected by filtration, and the crystalswere washed with a mixed solution of tetrahydrofuran (29.6 kg) and water(10.0 kg). The crystals were dried at 50° C. or less to obtain thecompound (18-a) (21.5 kg) (yield 88%). ¹H NMR (DMSO-d₆) 7.32-7.40 (m,4H), 7.26-7.32 (m, 1H), 7.15 (d, 2H), 6.86 (d, 2H), 3.73-3.87 (m, 3H),3.72 (s, 3H), 3.43 (ddd, 1H), 3.15 (dd, 1H), 2.90-3.10 (m, 2H), MS(ESI): m/z 330.1 [M+H]⁺

Example 5

A mixture of methanol (126.0 kg), the compound (18-a) (21.2 kg),cyclopentanone (13.3 kg) and 10% palladium-carbon/water (2.24 kg, watercontent 53%) was stirred at 50° C. under a hydrogen atmosphere of 0.60MPa for 21 hours. The reaction mixture was filtered through Celite andwashed with 50° C. methanol (42.3 kg). The filtrates were concentratedat 55° C. to 42 L, and methanol (6.4 kg) was added to 64 L. After themixture was stirred at 50° C. for 30 minutes, isopropanol (66.6 kg) wasadded thereto, and the mixture was stirred at 50° C. for 30 minutes andat 20° C. for 30 minutes. The crystals were collected by filtration andthe crystals were washed with a mixed solution of isopropanol (22.3 kg)and methanol (11.0 kg). The crystals were dried at 60° C. or less toobtain the compound (7-a) (17.4 kg) (yield 93%). MS (APCI): m/z 308.3[M+H]⁺

Example 6

To a suspension of the compound (19) prepared according to theabove-mentioned preparation examples 1 to 10 (15.2 kg) and sodiumchloride (6.00 kg) in toluene (75.0 kg) were added at room temperaturean aqueous solution of sodium hydrogen carbonate in water (68.8 L) andwater (6.9 L) in that order, and the mixture was stirred at roomtemperature for 20 minutes. The aqueous layer was removed, and theorganic layer was washed with water (75.7 L) and concentrated. Toluene(74.4 kg) was added thereto and the mixture was concentrated to 35 L.The mixture was diluted with toluene (22.0 kg), and the compound (7-a)(8.60 kg), N,N-diisopropylethylamine (12.7 kg) and acetonitrile (6.70kg) were added thereto in that order at room temperature, and themixture was stirred at room temperature for 30 minutes. The mixture wascooled to 10° C. and propylphoshonic acid anhydride (26.7 kg) was addedthereto, and the reaction mixture was stirred for 13 hours. An aqueoussolution of potassium carbonate (6.00 kg) in water (43.0 L), water (8.6L) and ethyl acetate (38.8 kg) was added in that order at roomtemperature, and the mixture was stirred at 35° C. for 20 minutes. Theaqueous layer was removed, and the organic layer was washed with anaqueous solution of citric acid monohydrate (7.70 kg) in water (51.5 L)and concentrated, and isopropanol (67.4 kg) was added thereto and thenconcentrated. Isopropanol (67.6 kg) was added again thereto, andconcentrated to 35 L to obtain a solution of the compound (1′).

Example 7

The solution of the compound (1′) obtained in the Example 6 was dilutedwith isopropanol (13.0 kg), and an solution of 1,2-ethanedisulfonic acidhydrate (3.09 kg) in isopropanol (33.8 kg), and isopropanol (13.5 kg)were added thereto at 75° C., and the mixture was stirred at 75° C. for1 hour and at 5° C. for 1 hour. The solids were collected by filtration,and the solids were washed with isopropanol (33.8 kg). The solids weredried at 50° C. or less to obtain the compound (1) (20.6 kg) (yield94%). ¹H NMR (DMSO-d₆) 10.50 (br d, 1H), 7.34-7.64 (m, 2H), 7.21-7.33(m, 2H), 6.89-7.10 (m, 2H), 4.20-4.53 (m, 1H), 3.57-4.13 (m, 11H), 2.50(m, 17H), 1.39-2.30 (m, 11H), MS (ESI): m/z 690.4 [M+H]⁺

Next, the formed solids were collected by filtration and dried underreduced pressure. The obtained solids were subjected to a powder X-raystructural analysis, and were confirmed to be crystals (see FIG. 1).

Measuring Device: D8 DISCOVER (Bruker AXS)

Operation Condition:

X-ray tube: Ceramic tube, copper, tube voltage: 40 kv, tube current: 40mA

Incident optical system: Goebel mirror

Photodetector: VANTEC2000

Sample stage: UMC150 xyz

Measuring range: 2θ=5 to 35°

The obtained crystals showed diffraction patters as indicated in Table 1as a diffraction angle (2θ±0.2°) in the above-mentioned powder X-raystructural analysis. The compound of the present invention have thefollowing characteristic diffraction patterns as diffraction angle(2θ±0.2°): at least 8.298, 14.198, 16.776, 17.102, 20.972, 22.658, and24.959.

TABLE 1 Peak No. 2θ (°) 1 8.003 2 8.298 3 9.333 4 11.245 5 11.930 611.964 7 12.459 8 13.460 9 13.772 10 13.774 11 14.198 12 15.437 1315.962 14 16.180 15 16.776 16 17.102 17 17.427 18 17.687 19 18.704 2019.538 21 19.646 22 20.439 23 20.972 24 21.522 25 22.658 26 23.378 2724.065 28 24.450 29 24.959 30 25.344 31 26.275 32 26.881

Alternative Method of Example 7

To a solution of the compound (1′) (276 mg) in ethanol (1.4 mL) wasadded 1,2-ethanedisulfonic acid hydrate (38 mg), and the mixture wasstirred at room temperature for 40 minutes. The crystals were collectedby filtration, and the crystals were washed with ethanol (0.84 mL)twice. The crystals were dried at 40° C. or less to obtain the compound(1) (178 mg) (yield 57%), and an elemental analysis of the crystals weremeasured.

TABLE 2 C H N F S Theoretical value 58.15 6.42 5.35 9.68 4.08 ofcompound (1) Measured value of 57.00 6.40 5.22 9.49 4.03 Crystal

Example 8

To a suspension of the compound (1) (19.3 kg) in ethyl acetate (86.6 kg)were added at room temperature a solution of potassium carbonate (3.40kg) in water (77.0 L) and water (19.3 L) in that order, and the mixturewas stirred at room temperature for 20 minutes. The aqueous layer wasremoved, and the organic layer was washed with water (96.3 L) twice, andconcentrated to 35 L. Ethanol (75.9 kg) was added thereto, and themixture was concentrated to 35 L. Ethanol (45.4 kg) was added thereto,and insoluble materials were filtered off, and ethanol (30.2 kg) wasadded thereto, and the mixtures were concentrated to 35 L. The mixturewas diluted with ethanol (17.9 kg) to 58 L, and 24% aqueous sodiumhydroxide solution (6.1 kg) and water (15.6 kg) were added in that orderat room temperature, and the mixture was stirred for 5 hours at roomtemperature to obtain the compound (11). MS (ESI): m/z 676.6 [M+H]⁺

Alternative Method of Example 8

To a suspension of the compound (1) (37.1 kg) in ethyl acetate (167.5kg) were added at room temperature an aqueous solution of potassiumcarbonate (6.5 kg) in water (148.3 L) and water (36.8 L) in that order,and the mixture was stirred at room temperature for 15 minutes. Theaqueous layer was removed, and the organic layer was washed with water(186 L) twice, and ethyl acetate (67.2 kg) was added thereto, andinsoluble materials were filtered off. The filtrates were concentratedto 78 L, and ethanol (146.5 kg) was added thereto, and the mixture wasconcentrated to 78 L. Ethanol (146.9 kg) was added thereto, and themixture was concentrated to 56 L. The mixture was diluted with ethanol(44 kg) and 24% aqueous sodium hydroxide solution (8.7 kg) and water(30.1 kg) were added in that order at room temperature, and the mixturewas stirred at 40° C. for 5 hours to obtain the compound (11).

Next, the preparation example of the compound (19) described in Example6 is shown.

Preparation Example 1

Potassium carbonate (26.1 kg) was dissolved in water (101.5 L), and thecompound (19-2) (18.4 kg), toluene (75.2 kg) and the compound (19-1)(14.8 kg) were added thereto in that order at room temperature, and thereaction mixture was stirred at 85° C. for 22 hours. After the mixturewas cooled to 40° C., the organic layer was collected by separating themixture with a separatory funnel, and water (101.5 L) and citric acidmonohydrate (14.5 kg) were added thereto at room temperature, and themixture was stirred. To the organic layer collected by separating with aseparatory funnel was added water (101.5 L) at room temperature, and themixture was stirred, and the organic layer collected by separating witha separatory funnel was concentrated at 50° C. to 60 L. Toluene (47.7 g)was added the concentrated residue, and the mixture was concentrated at50° C. to 30 L to obtain the compound (19-3).

Preparation Example 2

To a solution (30 L) of the compound (19-3) obtained in the PreparationExample 1 were added at room temperature nitromethane (47.0 kg), toluene(12.8 kg) and 28% solution (0.45 kg) of sodium methoxide in methanol inthat order, and the reaction mixture was stirred for 4 hours. Themixture was cooled to −5° C., and toluene (102.3 kg), methanesulfonylchloride (13.2 kg) and triethylamine (17.1 kg) were added in that order,and the mixture was stirred for 1 hour. Water (29.7 L) was added theretoat room temperature, and the mixture was stirred, and the organic layercollected by separating with a separatory funnel was concentrated at 50°C. to 120 L. Toluene (79.5 kg) was added to the concentrated residue,and the mixture was concentrated at 50° C. to 120 L. Toluene (77.0 kg)was added to the concentrated residue again, and the mixture wasconcentrated at 50° C. to 120 L to obtain a solution of the compound(19-4).

Preparation Example 3

To a solution (120 L) of the compound (19-4) obtained in the PreparationExample 2 were added at room temperature water (29.6 L), sodium hydrogencarbonate (2.96 kg) and dimethyl malonate (17.3 kg) and the compound(19-5) (0.95 kg) in that order, and the reaction mixture was stirred for19 hours. The organic layer was collected at 45° C. by separating with aseparatory funnel, and concentrated at 50° C. to 60 L. 2-Propanol (92.7kg) was added to the concentrated residue, and the mixture wasconcentrated at 65° C. to 90 L. 2-Propanol (93.5 kg) was added to theconcentrated residue again, and the mixture was concentrated at 65° C.to 90 L. After the mixture was cooled to 25° C., the mixture was stirredfor 16 hours. Further, after the mixture was cooled to −9° C. andstirred for 2 hours, the crude crystals were collected by filtration,and washed with water (147.8 L). The crude crystals were dissolved in1,2-dimethoxyethane (106.3 kg) at room temperature, and the mixture wasconcentrated at 50° C. to 50 L. 1,2-Dimethoxyethane (107.0 kg) was addedto the concentrated residue, and the mixture was concentrated at 50° C.to 50 L. 1,2-Dimethoxyethane (106.2 kg) was added to the concentratedresidue again, and the mixture was concentrated at 50° C. to 50 L toobtain a solution of the compound (19-6).

Preparation Example 4

To a solution (50 L) of the compound (19-6) obtained in the PreparationExample 3 were added at room temperature 1,2-dimethoxyethane (91.6 kg),5% rhodium-carbon (water content 56.3%, 10.6 kg) and acetic acid (2.99kg) in that order, and the reaction mixture was pressurized (0.6 MPa)with hydrogen gas at 60° C., and the mixture was stirred for 20 hours.After the mixture was cooled to 25° C., the solids in the reactionmixture were filtered off to obtain the filtrates. The filtered residueswere washed with 1,2-dimethoxyethane (114.8 kg), and the washedsolutions were combined with the filtrates, and the mixture wasconcentrated at 50° C. to 60 L. 1,2-Dimethoxyethane (115.0 kg) was addedto the concentrated residues, and mixture was concentrated at 50° C. to53 L. 1,2-Dimethoxyethane (114.9 kg) was added to the concentratedresidues again, and the mixture was concentrated at 50° C. to 53 L. Theconcentrated residues were cooled to room temperature, and1,2-dimethoxyethane (11.5 kg) was added thereto to obtain theconcentrated solution of the compound (19-7). The concentrated solutionwas mixed with the concentrated solution (scale 1.0 time) of thecompound (19-7) which was similarly prepared according to theabove-mentioned operations, and 1,2-dimethoxyethane (69.1 kg) was addedthereto. The mixture was concentrated at 50° C. to 110 L, and methanol(6.76 kg) and 1,2-dimethoxyethane (48.8 kg) were added thereto at roomtemperature in that order to obtain a solution (179 L) of the compound(19-7).

Preparation Example 5

To a suspension of sodium borohydride (7.99 kg) in 1,2-dimethoxyethane(146.7 kg) were added at 45° C. the solution of the compound (19-7)prepared in Preparation Example 4 and 1,2-dimethoxyethane (49.1 kg) inthat order, and the reaction mixture was stirred for 1 hour, and thencooled to room temperature. This reaction solution and1,2-dimethoxyethane (25.0 kg) were added at 25° C. to an aqueoussolution of ammonium chloride (45.2 kg) in water (169.0 kg) in thatorder. Ethyl acetate (235.7 kg) was added thereto at room temperature,and the mixture was stirred. The organic layer was collected byseparating with a separatory funnel, and water (112.3 L) was addedthereto at room temperature, and the mixture was stirred, and theorganic layer that was collected by separating with a separatory funnelwas concentrated at 50° C. to 170 L. Ethyl acetate (253.7 kg) was addedto the concentrated residue and the mixture was concentrated at 50° C.to 170 L. Heptane (231.5 L) was added thereto at 50° C., and the mixturewas stirred for 0.7 hours, and then cooled to 10° C., and stirred for 15hours. The crystals were collected by filtration, and the crystals werewashed with mixed solution of ethyl acetate (25.6 kg) and heptane (58.0kg) that was cooled to 10° C., and further with room temperature water(112.4 L). The crystals were dried at 50° C. to obtain the compound(19-8) (30.2 kg) (yield 44% based on the compound (19-1)).

Preparation Example 6

To a solution of the compound (19-8) (29.0 kg) in 1,2-dimethoxyethane(163.6 kg) was added at 10° C. a solution of methyl trifluoromethanesulfonate (16.1 kg) in 1,2-dimethoxyethane solution (87.9 kg), and thereaction mixture was stirred for 2 hours. After sodium tetrahydroborate(2.5 kg) was added at 0° C. to the reaction mixture, the mixture wasstirred at 10° C. for 2 hours. After triethylamine (16.6 kg) was addedthereto, a solution of di-tert-butyl dicarbonate (13.6 kg) in1,2-dimethoxyethane (25.0 kg) was added thereto, and the mixture wasstirred for 2 hours. The mixture was further stirred at 45° C. for 2hours, and then cooled to 25° C. Toluene (175.7 kg) was added thereto,and the organic layer was collected by separating with a separatoryfunnel, and an aqueous solution of ammonium chloride (20.3 kg) in water(182.7 L) was added thereto, and the organic layer was collected byseparating with a separatory funnel. Next, the organic layer was washedwith an aqueous solution of sodium hydrogen carbonate (5.8 kg) in water(110.2 L) and concentrated to 104 L to obtain the compound (19-9).

Preparation Example 7

To a suspension of N,N-dimethylformamide (97.9 kg), sodium hydroxide(15.7 kg) and toluene (18.0 kg) were added at −10° C. iodomethane (37.2kg), N,N-dimethylformamide (13.1 kg), and the solution of compound(19-9) obtained in the Preparation Example 6 (104 L) in that order, andthe reaction mixture was stirred at 0° C. for 10 hours. Water (117.6 L),triethylamine (26.5 kg), and toluene (90.0 kg) were added thereto, andthe organic layer was collected by separating with a separatory funnel.The organic layer was washed with an aqueous solution of ammoniumchloride (41.5 kg) in water (373.7 L) twice, and successively with anaqueous solution of sodium hydrogen carbonate (10.4 kg) in water (197.2L) to obtain a solution of the compound (19-10).

Preparation Example 8

To the whole amount of the solution of compound (19-10) obtained in thePreparation Example 7 was added at 40° C. a solution of potassiumhydroxide (17.3 kg) in methanol (213.6 L), and the mixture was stirredat 65° C. for 18 hours. The mixture was cooled to 50° C., and water(106.8 L) ad heptane (121.8 kg) were added thereto, and the aqueouslayer was collected by separating with a separatory funnel. An aqueoussolution of methanol (10.7 L) in water (7.1 L) and toluene (110.4 kg)were added thereto in that order. An aqueous solution of concentratedhydrochloric acid (39.8 kg) in water (159.7 L) was added thereto at 10°C., and the mixture was stirred and the organic layer was then collectedby separating with a separatory funnel to obtain the compound (19-11).

Preparation Example 9

Acetyl chloride (41.2 kg) was added at −10° C. to methanol (127.6 L),and then the whole amount of the solution of compound (19-11) obtainedin the Preparation Example 8 and the methanol (16.0 L) were addeddropwise thereto at 15° C. The reaction mixture was stirred at 20° C.for 4 hours, and methanol (16.0 L) was added thereto. Twenty-four (24)%aqueous sodium hydroxide solution (80.9 kg), water (129.8 L) and anaqueous solution of sodium carbonate (13.9 kg) in water (127.7 L) wereadded thereto in that order, and the mixture was stirred while mixing,and the organic layer was collected by separating with a separatoryfunnel. The organic layer was washed with an aqueous solution of sodiumchloride (9.6 kg) in water (95.7 L) to obtain a solution of the compound(19-12).

Preparation Example 10

To the solution of compound (19-12) obtained in the Preparation Example9 were added toluene (55.2 kg), ethanol (75.6 kg) and 2-methyl malonate(4.9 kg), and the reaction mixture was stirred at 15° C. to 8° C. for 8hours. The crystals were collected by filtration, and washed with asolution of ethanol (12.4 kg) in toluene (27.8 kg) that was cooled to 8°C., and dried at 50° C. to obtain the compound (19) (15.3 kg) (yield 45%based on the compound (19-8)).

Example 1 of Experiment

The compound (1′) (20 mg) was dissolved in various kinds of organicsolvents (100 μL), and any acid as indicated in Table 1 (molarequivalent ratio: 1) was added, and the completedly dissolved sampleswere left to stand. The results are shown in Table 3 below. As shown inTable 3, only in the case of the combination of 1,2-ethanedisulfonicacid dihydrate and ethanol, only solids could be obtained among thestudied conditions.

TABLE 3 Solvent Methyl 2- ter- Methyl- 1,2- Methyl butyl tetra-Dimethoxy- Isopropyl Tetra- isopropyl Acid ether hydrofuran Ethanolethane acetate hydrofuran ketone Acetonitrile 2M x x x — — — — —Hydrochloric acid/ methanol Phosphoric x x x — — — — — acid Sulfuric x xx — — — — — acid Maleic acid x x x — — — — — Fumaric — x x — — — — —acid Citric acid x x x — — — — — monohydrate L-tartaric — x x — — — — —acid Malonic — x x — — — — — acid (+)-Camphor — x x — — — — — acid (+)-x x x — — — — — Dibenzoyl- D-tartaric acid monohydrate 1,5- — — x — — —— — Naphthalene disulfonic acid (−)- — x x — — — — — Camphor- sulfonicacid Methane- — x x — — — — — sulfonic acid 1,2- — x ∘ x x x x xEtanedi- sulfonic acid dihydrate

In the Table, “-” means that an acid was not dissolved, or the studywasn't conducted, “x” means that only solids couldn't be obtained, and“o” means that only solids could be obtained.

Example 2 of Experiment

With respect to the below-mentioned compound (2-a), compound (20-a) andcompound (21-a), as shown in Examples 2-1 to 2-3, the cyclization ofthese compounds with the compound (16) was conducted, and thestereoselectivity of the products were compared.

Example 2-1 of Experiment

To a suspension of the compound (2-a) (6.75 g) in dichloromethane (30mL) were added at room temperature a solution of compound (16) (14.1 g)in dichloromethane (30.0 mL) and trifluoroacetic acid (0.152 mL) in thatorder, and the reaction mixture was stirred for 30 minutes under heatreflux. The mixture was stood to cool to room temperature, and anice-cooled aqueous citric acid (25.0 g) in water (250 mL) was addedthereto, and the mixture was extracted with chloroform (100 mL) twice.The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and dried over anhydrous magnesium sulfate. Thedrying agent was removed, and the solvents were evaporated under reducedpressure. The resulting residues were triturated with isopropyl ether toobtain a mixture of the compound (17-a) and the compound (17-b) (7.39 g)(yield 79%). The diastereomer ratio in the obtained mixture was measuredwith NMR analysis, and as a result, the ratio was that of the compound(17-a):the compound (17-b)=5.1:1.

Example 2-2 of Experiment

To a solution of the compound (20-a) (928 mg) and the compound (16)(2.15 g) in dichloromethane (9.0 mL) was added at room temperaturetrifluoroacetic acid (0.023 mL), and the reaction mixture was stirredunder heat reflux. The mixture was stood to cool to room temperature,and an aqueous solution of citric acid (3.0 g) in water (30 mL) wasadded thereto under ice-cooling, and the mixture was extracted withchloroform. The organic layer was washed with saturated aqueous sodiumhydrogen carbonate solution, and dried over anhydrous magnesium sulfate.The drying agent was removed and the solvents were evaporated underreduced pressure. The resulting residues were purified by silica gelchromatography (hexane:ethyl acetate=9:1 to 2:1) to obtain a compound(22-a) (588 mg) (yield 44%) and a compound (22-b) (253 mg) (yield 19%).The diastereomer ratio was that of the compound (22-a):the compound(22-b) =2.3:1.

Example 2-3 of Experiment

To a mixture of the compound (21-a) (34.7 g), the compound (16) (58.0 g)and chloroform (200 mL) was added at room temperature trifluoroaceticacid (0.940 mL), and the reaction mixture was stirred at roomtemperature for 30 minutes and under heat reflux for 30 minutes. Themixture was stood to cool to room temperature, and the compound (14)(11.6 g) and trifluoroacetic acid (0.188 mL) were added thereto, and thereaction mixture was stirred under heat reflux for 30 minutes. Themixture was stood to cool to room temperature, and an aqueous solutionof ice-cooled citric acid (100 g) in water (1.00 L), and the aqueouslayer was removed. The organic layer was washed with saturated aqueoussodium hydrogen carbonate solution, and dried over anhydrous magnesiumsulfate. The drying agent was removed, and the solvents were evaporatedunder reduced pressure. The resulting residues were triturated withdiisopropyl ether (150 mL) to obtain a mixture of a compound (23-a) anda compound (23-b) (35.5 g). The resulting mixture was purified by silicagel chromatography (hexane:ethyl acetate=4:1 to 1:1) to obtain thecompound (23-a) (20.3 g) (yield 43%) and the compound (23-b) (10.5 g)(yield 22%). The diastereomer ratio was that of the compound (23-a):thecompound (23-b) =1.9:1.

As a result of the above-mentioned Examples 2-1 to 2-3, the diastereomerratio of the reaction products was shown in Table 4, and it was thusfound that the reaction of the compound (2-a) with the compound (16)which was described in Example 2-1 showed the highest stereoselectivity.Namely, it was found that the compound (17-a) as an intermediatecompound for the compound of the present invention, which is describedin Example 3 can be obtained effectively in terms of stereoselectivity.

TABLE 4 Example Compound to be reacted Diastereomer ratio of No. withcompound (16) Product 2-1 Compound (2-a)  5.1:1 2-2 Compound (20-a)2.3:1 2-3 Compound (21-a) 1.9:1

INDUSTRIAL APPLICABILITY

The compound of the present invention has excellent crystallinity andcan be thus applied as an intermediate compound for a compound that isuseful for prophylaxis or treatment of various diseases or conditions inwhich an activation of melanocortin receptor is involved. Also themethod of the present invention can be applied as a method showingexcellent stereoselectivity for preparing the compound of the presentinvention, and as a result, can be applied as a method showing excellentstereoselectivity for preparing compound that is useful for prophylaxisor treatment of various diseases or conditions in which an activation ofmelanocortin receptor is involved.

1. Methyl1-{2-[(3S,4R)-1-[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-carbonyl]-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylate1/2 ethane-1,2-disulfonic acid, which is represented by formula (1):


2. A method for preparing the compound (1), which is shown by thereaction scheme:

wherein R¹ represents a protecting group for an amino group which is analkyl having one to six carbon atoms which may be optionally substitutedwith aryl in which the aryl may be optionally substituted with alkoxyhaving one to six carbon atoms, R² represents a silyl which issubstituted with one to three alkyl having one to six carbon atoms or acyano, and R³ represents an alkoxy having one to six carbon atoms.

, wherein the method comprises the following steps: (a) a step ofreacting a compound (2-a) with a compound (3) to obtain a compound (4-a)or salts thereof, (b) a step of hydrolyzing a compound (4-a) or saltsthereof to obtain a compound (5-a) or salts thereof, (c) a step ofremoving a protecting group R¹ of an amino group in the compound (5-a)or salts thereof, followed by reacting with a compound (6) to obtain acompound (7-a) or salts thereof, (d) a step of condensing the compound(7-a) or salts thereof with a compound (8) or salts thereof to obtain acompound (1′) or salts thereof, and (e) a step of reacting the compound(1′), or the compound (1′) which is obtained by desalting of a salt ofthe compound (1′), with a compound (9) to obtain a compound (1).
 3. Themethod according to claim 2 wherein R¹ represents a benzyl, R²represents a trimethylsilyl, and R³ represents a methoxy.
 4. A compoundrepresented by formula (4):

wherein R⁴ represents an alkyl having one to six carbon atoms which maybe optionally substituted with aryl in which the aryl may be optionallysubstituted with alkoxy having one to six carbon atoms, or saltsthereof.
 5. A compound represented by formula (4-a):

wherein the symbols are the same as defined in claim 4, or saltsthereof.
 6. A compound represented by formula (5):

wherein R⁵ represents an alkyl having one to six carbon atoms which maybe optionally substituted with aryl in which the aryl may be optionallysubstituted with alkoxy having one to six carbon atoms, or saltsthereof.
 7. A compound represented by formula (5-a):

wherein the symbol is the same as defined in claim 6, or salts thereof.8. A compound represented by formula (2):

or salts thereof.
 9. A compound represented by formula (2-a):

or salts thereof.
 10. A compound (1′):

or salts thereof.
 11. A method for preparing a compound represented byformula (11):

or pharmaceutically acceptable salts thereof, which comprises a step ofhydrolyzing methyl1-{2-[(3S,4R)-1-[(3R,4R)-1-cyclopentyl-3-fluoro-4-(4-methoxyphenyl)pyrrolidine-3-carbonyl]-4-(methoxymethyl)pyrrolidin-3-yl]-5-(trifluoromethyl)phenyl}piperidine-4-carboxylate1/2 ethane-1,2-disulfonic acid or salts thereof, and optionally, asneeded, a step of subjecting to a salt-forming treatment.